Commentary (Giles/Kantarjian): Biology and Treatment of Chronic Myelogenous Leukemia

Drs. Enright and McGlave succinctly review the biology of chronic myelogenous leukemia (CML) and highlight the therapeutic role of allogeneic stem-cell transplantation. Two points, however, warrant further discussion.The first is that a regimen containing interferon-alfa (Intron A, Roferon-A) is optimal front-line therapy for the great majority of CML patients.[1] The second is that use of an interferon-alfa-based regimen prior to allogeneic stem-cell transplantation does not adversely affect post-transplant mortality, morbidity, or anti-CML efficacy.

Interferon-Alfa-Based Regimens Are Optimal Front-Line Therapy

Of 274 patients treated with interferon-alfa-based regimens at The M.D. Anderson Cancer Center, 80% achieved complete hematologic remission (CHR), and 58% had a cytogenetic response (complete in 26%, major in 38%)[1] The median survival was 89 months (confidence interval, 66 to 102 months). Achieving a cytogenetic response after 12 months of therapy was associated with a statistically longer survival by landmark analysis-5-year survival rates dated from 12 months into therapy were 90% for complete cytogenetic response, 88% for partial cytogenetic response, 76% for minor cytogenetic response, and 38% for other response categories.

A multivariate analysis incorporating major cytogenetic response as a time-dependent variable showed it to be an independent prognostic factor for survival; patients achieving a major cytogenetic response had a 0.21 risk of death per unit time, compared with the total study group. Confirming this finding is the observation of the favorable impact of cytogenetic response within prognostic risk groups by landmark analysis. Survival improvement is due to a delay in progression to the blastic phase and is independent of pretreatment characteristics. Studies from many single institutions and cooperative groups have confirmed the efficacy of interferon-alfa in CML.[2]

Recently, four randomized trials comparing interferon-alfa with conventional chemotherapy have been reported.[3-6] Table 1 summarizes the results of large interferon-alfa studies in terms of study design, patient number, intended and delivered interferon-alfa dose, CHR and cytogenetic response profiles, and survival results.[1,3-10] In three of the prospective, randomized studies, interferon-alfa therapy prolonged survival and delayed progression to the blastic phase when compared with conventional therapy.[3,5,6] In all four randomized trials, interferon-alfa therapy produced a higher rate of major and complete cytogenetic response than did conventional chemotherapy.

Cytogenetic response to interferon-alfa was generally correlated with survival, and both studies that failed to show this prognostic association had a low rate of major cytogenetic responses, possibly because of low actual doses of interferon-alfa administered.[4,9] Two other studies showing a correlation between cytogenetic response and survival also reported that patients treated with interferon-alfa who did not achieve a cytogenetic response had survivals equivalent to patients receiving conventional chemotherapy.[5,11] The Medical Research Council study showed a longer survival duration for patientswho received interferon-alfa even if they did not achieve a cytogenetic response, but those who achieved a cytogenetic response lived longer than those who did not.[3]

Complete hemotologic response rates in similar study populations (ie, early chronic-phase CML) have ranged from 31% to 80%.[2-11] Some variability in the CHR rates may be due to
different response criteria or protocol treatment designs. This would not explain the large differences in the cytogenetic (18% to 58%), major cytogenetic (10% to 38%), and complete cytogenetic response (6% to 26%) rates. Differences in cytogenetic response results may be due to: (1) different risk group distributions; (2) patient and physician motivation; (3) the actual dose of interferon-alfa delivered; (4) the frequency of cytogenetic studies; (5) inclusion of advanced- or accelerated- phase patients, and (6) use of interferon-alfa monotherapy as induction, with consequent higher early dropout rates. When patients were analyzed for response to interferon-alfa and survival within risk groups, the data still showed an interferon-alfa-associated advantage in each risk group, suggesting that the dose-intensity of interferon-alfa increased the quality of cytogenetic response and prolonged survival.

Initial studies of interferon-alfa plus cytotoxic agents were conducted to determine whether patients who failed to achieve a CHR or cytogenetic remission on interferon-alfa alone might do so with combined therapy, and whether cytogenetic remission rates might improve with the increased myelosuppression associated with combination therapy. Combinations of interferon-alfa with hydroxyurea (Hydrea) and with cytarabine (ara-C) were initially investigated in patients with late chronic-phase disease. Data from a United Kingdom group and The M.D. Anderson Cancer Center indicated that both interferon-alfa/hydroxyurea and interferon-alfa/ara-C seemed to prolong late chronic phase, in contrast to treatment with interferon-alfa or the cytotoxics alone.[12,13] Subsequent studies indicated that interferon-alfa/cytotoxic combinations may be the optimal current therapy for patients with early chronic- phase disease (Table 2).[10,14-17]

In human malignancies, achieving a minimal tumor burden is a prerequisite for cure or for improvement of survival. The causal association between Philadelphia chromosome (Ph)-related molecular events and the development of CML suggests that a reduction in Ph-positive cells should be accepted as indicative of a reduced CML tumor burden. Reduction in tumor burden, as reflected by CHR, has been associated with significant survival prolongation in all studies in which it has been examined.[3,5,6,8]

Achieving a minimal cytogenetic tumor burden has also been associated with a significant survival advantage by landmark and/or multivariate analysis in the majority of studies to date. Thus, most current data suggest that achieving a minimal CML tumor burden, as reflected by hematologic and cytogenetic remissions, will have a favorable impact on outcome, and should be pursued as a therapeutic objective in future investigations.

Prior IFN-A Therapy Does Not Adversely Affect Allogeneic Stem-Cell Transplantation

Busulfan (Myleran) therapy prior to allogeneic stem-cell transplantation has been shown to have an adverse impact on post-transplant survival.[18] This is not the case with inteferon-alfa therapy prior to transplant. Data from Beelen et al suggesting that interferon-alfa therapy prior to allogeneic stem-cell transplantation might compromise outcome have not been reproduced in three other larger patient cohorts.[19,20-22] An analysis of data from the International Bone Marrow Transplant Registry (IBMTR) on 882 CML patients who had been treated with allogeneic stem-cell transplantation showed that interferon-alfa therapy prior to transplantation had no adverse impact on outcome.[21] Patients with a matched sibling donor available for allogeneic stem-cell transplantation may benefit from this strategy as first-line therapy, depending on individual center transplantation results.

Summary

Allogeneic stem-cell transplantation and interferon-alfa-based therapy have undoubtedly changed the natural history of CML. Despite these advances, most CML patients still die from the disease. Many patients do not qualify for an allogeneic stem-cell transplant, either because of age or lack of an appropriate donor, and only a fraction of patients achieve a complete cytogenetic response with interferon-alfa-based therapy. Prior treatment with interferon-alfa does not adversely affect allogeneic stem-cell transplantation outcome.

The optimal choice of therapy for CML patients depends on patient age, disease stage, availability of a HLA-compatible donor, patient preference, and tolerance of interferon-alfa therapy. The combination of interferon-alfa and ara-C is superior to interferon-alfa alone, and continuous administration of ara-C may be more effective than intermittent administration when the two drugs are combined[15].

Further understanding of the molecular biology of CML and of the molecular basis for the anti-CML effect of interferon-alfa should help guide the search for curative therapy.

References:

1. Kantarjian H, O'Brien S, Anderlini P, et al: Treatment of chronic myelogenous leukemia: Current status and investigational options. Blood 87:3069, 1996.

2. Kantarjian H, Giles F, O'Brien S, et al: Clinical course and therapy of chronic myelogenous leukemia with alpha interferon and chemotherapy. Hematol Oncol Clin North Am, 1997 (in press).

3. Allan N, Richards S, Shepherd P, et al: UK Medical Research Council randomized multicenter trial of interferon-an1 for chronic myeloid leukemia: Improved survival irrespective of cytogenetic response. Lancet 345:1392, 1995.

4. Hehlmann R, Heimpel H, Hasford J, et al: Randomized comparison of interferon-a with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 84:4064, 1994.

5. Italian Cooperative Study Group on Chronic Myeloid Leukaemia: Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukaemia. N Engl J Med 330: 820, 1994.

6. Ohnishi K, Ohno R, Tomonaga M, et al: A randomized trial comparing interferon-a with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 86:906, 1995.

7. Alimena G, Morra E, Lazzarino M, et al: Interferon alpha-2b as therapy for Ph'-positive chronic myelogenous leukemia: A study of 82 patients treated with intermittent or daily administration. Blood 72:642, 1988.

8. Mahon F, Fabères C, Boiron J, et al: High response rate using recombinant alpha interferon in patients with newly diagnosed chronic myeloid leukemia: Analysis of predictive factors
(abstract). Blood 88(suppl 1):638a, 1996.

9. Ozer H, George S, Schiffer C, et al: Prolonged subcutaneous administration of recombinant alfa-2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: Effect on remission duration and survival: Cancer and Leukemia Group B Study 8583. Blood 82:2975, 1993.

10. Guilhot F, Chastang C, Guerci A, et al: Interferon-alpha 2b and cytarabine increase survival and cytogenetic response in chronic myeloid leukemia: Results of a randomized trial (abstract). Blood 88(suppl 1):141a, 1996.

11. Kantarjian H, Smith T, O'Brien S, et al: Prolonged survival following achievement of cytogenetic response with alpha interferon therapy in chronic myelogenous leukemia. Ann Intern Med 122:254, 1995.

12. Giles F, Aitchison R, Syndercombe-Court D, et al: Recombinant alpha 2B interferon in combination with oral chemotherapy in late chronic phase chronic myeloid leukaemia. Leuk Lymphoma 7:99, 1992.

13. Kantarjian H, Keating M, Estey E, et al: Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-a and low-dose cytarabine. J Clin Oncol 10:772, 1992.

14. Arthur C, Ma D: Combined interferon alfa-2a and cytosine arabinoside as first-line treatment for chronic myeloid leukemia. Acta Haematol 89(Suppl 1):15, 1993.

15. Kantarjian H, O'Brien S, Keating M, et al: Interferon alpha and low-dose cytosine arabinoside therapy in Philadelphia chromosome-positive chronic myelogenous leukemia. Proc Am Soc Clin Oncol 16:13a, 1997.

16. Thaler J, Hilbe W, Apfelbeck U, et al: Interferon-alpha-2c and low dose ara-c for the treatment of patients with CML: Results of the Austrian multi-center phase II study. Leukemia Res 21:75, 1997.

17. Silver R, Szatrowski T, Peterson B, et al: Combined a-interferon and low dose cytosine arabinoside for Ph+ chronic phase chronic myeloid leukemia (abstract). Blood 88(suppl 1):638a, 1996.

18. Goldman J, Szydlo R, Horowitz MM, et al: Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 82:2235, 1993.

19. Beelen D, Graeven U, Elmaagacli A, et al: Prolonged administration of interferon-a in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood 85:2981, 1995.

20. Giralt S, Kantarjian H, Talpaz M, et al: Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 11:1055, 1993.

21. Horowitz MM, Giralt S, Szydlo R, et al: Effect of prior interferon therapy on outcome of HLA-identical sibling bone marrow transplants for chronic myelogenous leukemia in first chronic phase (abstract). Blood 88 (supp 1):682a, 1996.

22. Sheperd P, Richards S, Allan N: Survival after allogeneic bone marrow transplantation in patients randomized into a trial of IFN-a versus chemotherapy: No significant adverse effect of prolonged IFN-a administration (abstract). Blood 86(suppl 1):94, 1995.